Organized differentiation of epidermal cells is required for the functional integrity of the skin. Ichthyosis vulgaris is a skin disease with both autosomal recessive and dominant inheritance, which is characterized by scaling and flaky skin lesions. We have recently developed a mouse model with targeted disruption of the gene encoding the epithelial-specific small GTPase, Rab25. Rab25 and its molecular cousin Rabl la are critical regulators of the processes of membrane recycling of receptors, ion pumps and ion channels in epithelial cells. The Rab25 knockout mouse displays abnormalities in its tail consistent with the phenotype of ichthyosis vulgaris. In addition, the Rab25 gene in both human and mouse lies 0.4 cM from a group of genes designated the epidermal differentiation complex (EDC). Ichthyosis vulgaris in at least one cohort maps to this chromosomal region (lq21 in humans). Therefore, we have hypothesized that Rab25 expression may contribute to the pathophysiology of ichthyosis vulgaris. To examine this hypothesis, we will pursue two specific aims: First, we will characterize in detail the skin phenotype of the Rab25 knockout mice by examining immunohistochemical markers of skin differentiation and ultra structural correlates. Second, we will examine whether alteralions of Rab25 expression and/or localization are present in the skin of patients with ichthyosis vulgaris or other major skin diseases. In addition, we will determine whether patients from familial cohorts of ichthyosis vulgads have any mutations in the Rab25 gene that might lead to functional deletion or the creation of dominant mutant proteins. These investigations should allow us to test whether aberrant Rab25 expression is involved in the pathogenesis off ichthyosis vulgads. In addition, it will provide the first investigations of alterations in membrane recycling in skin diseases.